Ewing sarcoma and rhabdomyosarcoma are two highly aggressive primary cancers that afflict children and adolescents. Although conventional therapy can produce cures in ~70% of patients with localized tumors, the prognosis for patients with metastatic disease is much more dismal, with five-year survival rates of 30% or less. Oncolytic herpes viruses, which selectively target and destroy tumor cells, represent a novel anticancer therapy in development via both intratumoral and intravenous routes. Although these viruses hold great promise, their access to metastatic sites following systemic delivery is relatively low. Limited tumor uptake is likely due to numerous factors, among them poor transvascular penetration. In order to overcome this barrier, we are investigating the use of newly developed CendR peptides in conjunction with the attenuated oncolytic herpes simplex virus HSV1716, a virus currently in clinical cancer trials. The prototypical CendR peptide, internalizing Arginine-Glycine-Aspartic Acid (iRGD), and its newer more potent derivative Cys-X-iRGD, are cyclic peptides that contain two functional motifs: an RGD element that enhances tumor localization through its recognition and binding of ?v?3/5 integrins on tumor neovasculature, and the eponymous CendR motif, which potentiates tissue penetration through its interaction with the VEGF co-receptor neuropilin-1. Interestingly, previous studies have shown that these activities are not limited to the peptides themselves, but extend to molecular compounds and chemotherapeutic drugs either conjugated to them or even simply given concurrently. We hypothesize that the co-administration of a CendR peptide with virotherapy improves tumor-selective uptake of HSV1716, leading to improved therapeutic responses. To preliminarily test this concept, we administered a single 4 ?mol/kg dose of the iRGD peptide intravenously immediately prior to intravenous virus in mice harboring A673 sarcoma flank tumors. We observed a greater than two-fold enhancement of HSV1716 uptake into the tumor. In the proposed studies, we will examine what effect the use of CendR peptides have on the biodistribution of HSV1716 and how they influence extravasation of the virus into the tumor (aim 1), and what significance the peptides have on virotherapy efficacy in mouse tumor models, including a xenograft model of Ewing sarcoma and an immunocompetent model of rhabdomyosarcoma (aim 2). If this approach is successful, it could have broad implications for virotherapy of many types of cancers, as the features responsible for CendR peptide activity are nearly ubiquitous across solid tumors.